The primary goals of this K24 competing renewal application are to enable Christian Hopfer, M.D. to conduct career development activities to enhance his patient-oriented addiction research and to provide high-quality mentorship to early-career investigators. The renewal will enable Dr. Hopfer to have protected time to devote to career development and mentoring of clinical researchers. Dr. Hopfer was promoted to Full Professor of Psychiatry at the University of Colorado School of Medicine due to the success of his research, teaching, and clinical program. Dr. Hopfer's major goals of his initial award were accomplished with obtaining and leading a NIDA funded R25 medical student research education program, acting as the executive director of the Developmental Psychobiology Research Group (DPRG) whose affiliated T32 program was renewed, obtaining new research funding, and mentoring junior investigators. Dr.Hopfers' research plan for this renewal application involves continued work as a PI on NIDA funded research focused on understanding genetic and environmental influences on the progression or desistance of substance use disorders among high-risk youth utilizing a joint twin/family study design as well as understanding the impact of legal marijuana access on psychiatric and behavioral outcomes. He plans to expand his search for biomarkers for substance use disorders that have been previously conducted utilizing molecular genetic approaches to now include proteomic, metabolomics, RNA-seq, and lipidomic approaches. Dr.Hopfer mentors trainees in multiple areas of research training including: 1) Understanding clinical aspects of substance use and abuse, 2) Twin/family and molecular approaches to examining the etiology of substance use and correlated disorders, 3) Preparing scientific papers and presenting findings, 4) Developing and writing successful project proposals, and 5) conducting responsible research. He will accomplish his training mission through individual and group mentoring and collaborating with key colleagues with expertise in biostatistics and state of the art measurement technologies for identifying biomarkers of substance use.